As is known, d,1-.alpha.-tocopherol is a diastereoisomeric mixture of 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl-tridecyl)-6-chromanol (.alpha.-tocopherol), which is the most active and industrially most important member of the vitamin E group.
Many processes for the manufacture of d,1-.alpha.-tocopherol by the condensation of trimethylhydroqllinone (TMHQ) with isophytol (IP) in the presence of various catalysts or catalyst systems and in various solvents are described in the literature. These processes go back to the work of Karrer et al., Bergel et al. as well as Smith et al.: see Helv. Chim. Acta 21, 520 et seq. (1938), Nature 142, 36 et seq. (1938); Science 88, 37 et seq. (1938); and J. Am. Chem. Soc. 61, 2615 et seq. (1939).
While Karrer et al. carried out the synthesis of d,1-.alpha.-tocopherol from TMHQ and phytyl bromide in the presence of anhydrous zinc chloride (ZnCl.sub.2, a Lewis acid), not only Bergel et al. but also Smith et al. used TMHQ and phytol as starting materials. In the following years mainly modifications, e.g. alternative solvents and Lewis acids, were developed. From the work of Karrer et al., a process for the manufacture of d,1-.alpha.-tocopherol was developed in 1941 in which the condensation of TMHQ with IP was carried out in the presence of a ZnCl.sub.2 /hydrochloric acid (HCl) catalyst system: see U.S. Pat. No. 2,411,969. Later publications, e.g. Japanese Patent Publications (Kokai) 54380/1985, 64977/1985 and 226979/1987 [Chemical Abstracts (C.A.) 103, 123731s (1985), C.A. 103, 104799d (1985) and C.A. 110, 39217r (1989)], describe this condensation in the presence of zinc, ZnCl.sub.2 and a Bronsted (protonic) acid such as a hydrohalic acid, e.g. HCl, trichloroacetic acid, acetic acid and the like, especially ZnCl.sub.2 /HCl, as the catalyst system.
Disadvantages of these and further published processes featuring ZnCl.sub.2 in combination with a Bronsted acid include the corrosive properties of the acids and the contamination of the waste water with zinc ions as a result of the large amount of ZnCl.sub.2 required for the catalysis.
The manufacture of d,1-.alpha.-tocopherol by the reaction of TMHQ with phytyl chloride, phytol or isophytol in the presence of boron trifluoride (BF.sub.3) or its etherate (BF.sub.3.Et.sub.2 O) is described in German Patent Nos. 960720 and 1015446, as well as in U.S. Pat. Nos. 3,444,213 and 4,634,781. These reactions are not ideal because BF.sub.3 also has corrosive properties.
Furthermore, the condensation of TMHQ with IP or another phytyl derivative in the presence of a Lewis acid, e.g. ZnCl.sub.2, BF.sub.3 or aluminum trichloride (AlCl.sub.3), a strong acid, e.g. HCl, and an amine salt as the catalyst system is described in European Patent Publication (EP) 100471. In an earlier patent publication, DOS 2606830, the IP or phytol is pretreated with ammonia or an amine before the condensation with TMHQ in the presence of ZnCl.sub.2 and an acid is effected. In both cases, corrosion problems occur which diminish the usefulness of these reactions.
A further method for the manufacture of d,1-.alpha.-tocopherol from TMHQ and IP includes using an isolated TMHQ-BF.sub.3 or -AlCl.sub.3 complex as the catalyst and a solvent mixture featuring a nitro compound (DOS 1909164). This process avoids to a large extent the formation of undesired by-products because it involves mild reaction conditions. The yield of d,1-.alpha.-tocopherol, based on IP and the use of the solvent mixture methylene chloride/nitromethane, is given as 77%. However, the use of such a solvent mixture is disadvantageous.
The manufacture of d,1-.alpha.-tocopherol by the condensation of TMHQ with IP using cation exchange complexes of metal ions (Zn.sup.2+, Sn.sup.2+ and Sn.sup.4+) is disclosed in Bull. Chem. Soc. Japan 50, 2477-2478 (1977). Among other disadvantages, these reactions produce unsatisfactory yields.
The use of macroreticular ion exchangers, e.g. Amberlyst.RTM. 15 as the catalyst for the condensation of TMHQ with IP, is described in U.S. Pat. No. 3,459,773.
EP 603695 describes the manufacture of d,1-.alpha.-tocopherol in liquid or supercritical carbon dioxide by the condensation of TMHQ with IP in the presence of acidic catalysts, such as ZnCl.sub.2 /HCl and ion exchangers.
The condensation reaction which takes place in the presence of a catalyst system containing iron(II) chloride, metallic iron and HCl gas is described in DOS 2160103 and U.S. Pat. No. 3,789,086. These reactions form fewer byproducts compared with the aforementioned process using ZnCl.sub.2 /HCl. These reactions, however, are prone to corrosion problems and chloride contamination.
An alternative to the condensation of TMHQ with IP to d,1-.alpha.-tocopherol includes using trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although this process avoids the use of HCl, the alternative catalyst is relatively expensive, and thus not commercially viable.
The use of heteropolytungsten acids as catalysts for the condensation of TMHQ with IP was described for the first time in React. Kinet. Catal. Lett. 47(1), 59-64 (1992). In these reactions, d,1-.alpha.-tocopherol was reportedly obtained in about 90% yield using various solvents.
A further process described in EP 658552; Bull. Chem. Soc. Japan 68, 3569-3571 (1995) for the synthesis of d,1-.alpha.-tocopherol is based on the use of a scandium, yttrium or lanthanide fluorosulphonate, nitrate or sulfate, e.g. scandium trifluoromethanesulphonate. When up to about 10% excess of IP is used, this process reportedly provides yields up to 98%.
The use of ion exchanged bentonite, montmorillonite or saponite through treatment with, e.g. scandium chloride and other metal salts (yttrium, lanthanum, etc.) as the catalyst for the condensation of TMHQ with IP has been described. Such a reaction is disadvantageous because of the need for a large amount of catalyst: see EP 677520; Bull. Chem. Soc. Japan 69, 137-139 (1996).
According to the Examples of EP 694 541, the condensation of TMHQ with IP to form .alpha.-tocopherol reportedly can be achieved in high yields and with a high product purity when solvents such as carbonate esters, fatty acid esters and mixed solvent systems are employed. In these reactions, catalysis is effected by ZnCl.sub.2 /HCl. These reactions suffer from several drawbacks, including contamination of the waste water by zinc ions and the requirement for the use of large "catalyst amounts" of ZnCl.sub.2.
According to WO 97/28151, the acid-catalyzed condensation of TMHQ with IP can reportedly be performed using a cyclic carbonate or .alpha.-lactone as the solvent. The preferred catalyst is a mixture of ortho boric acid and oxalic, tartaric or citric acid, or boron trifluoride etherate.
In summary, all the reactions producing d,1-.alpha.-tocopherol described in the references cited above suffer from considerable disadvantages, including corrosion problems when acid catalysts such as boron trifluoride are used; toxicity problems when boron trifluoride adducts are used; and contamination of the waste water with metal ions when iron or zinc is used. Moreover, in some of the processes set forth above, the formation of undesired byproducts, e.g. phytyltoluene and chlorophytols, is an especially serious problem.